Our overall hypothesis is that insulinotropic peptides from the GI tract ("incretins") and somatostatin-28 (S-28), a "decretin", modulate insulin secretion in a coordinate manner during absorption and assimilation of nutrients. We also postulate that substrate-induced release of the "incretin" glucagon-like peptide-1 7-36 amide [tGLP-1] from enterocytes is not a direct process but rather is indirectly mediated through neurotransmitters secreted from intestinal cells responding specifically to luminal nutrients. A derivative hypothesis is that tGLP-1 also has an ancillary function to enhance glucose disposition during nutrient absorption. specific questions include: 1) Do intestinal endocrine epithelial cells (enterocytes) that secrete GIP, tGLP-1 and S-28 respond directly to specific substrates? 2) Do "incretins" and S-28 modulate the kinetics of insulin secretion during nutrient absorption? 3) Does tGLP-1 modulate postprandial glucose disposition independent of its insulinotropic action? a) if so, does it affect peripheral glucose utilization and/or hepatic glucose production (HGO), and b) are these putative actions dependent on insulin and/or the release of glucagon. These hypotheses and questions are derived from evidence in vitro and in vivo that GIP and tGLP-1 potentiate glucose-mediated insulin secretion whereas S-28 inhibits it. In vitro data suggests that this may result from a shift in threshold and rate of insulin release and that there may be subpopulations of B-cells which respond at different thresholds. Furthermore, indirect evidence suggests that the release of the enteric peptides during nutrient intake may not be due to a direct effect of the substrates on their release from specific enterocytes. To address these questions we will evaluate the effects of tGLP-1 and S-28 separately and together on the threshold of rate of insulin secretion in isolated islets and in humans. The physiologic role of S-28 as a putative modulator of insulin secretion in vivo will be indirectly evaluated in humans using omeprazole and loxiglumide, recently discovered inhibitors of S-28 secretion. to determine if nutrients directly elicit enteropeptide secretion or do so via receptors on neural cells which then signal enterocytes, we will test the effects of specific nutrient constituents and neurotransmitters in cultured monkey enterocytes. Recently published data implies an additional, unexpected action of tGLP-1 in either potentiating or mimicking the action of insulin on glucose disposition in humans. We will examine this issue in humans by measuring glucose disposal and HGO isotopically, at clamped insulin and glucagon levels, during tGLP-1 infusions. The results of the experiments should provide a more comprehensive view of the physiologic importance of the "enteroinsular axis" in fuel homeostasis.